D1 And D2 Receptors and circling behavior in rats with unilateral lesion of the entopeduncular nucleus

The role of D₁ and D₂ striatal dopamine receptors on circling behavior was studied in a normosensitive model obtained by unilateral kainic acid lesion of the entopeduncular nucleus. In this model, the sensitivity of striatal dopamine receptors was preserved, because kainic acid destroyed the neurons of the entopeduncular nucleus and left undamage the fibers of passage and axon terminals. Systemic administration of SKF 38393 to these animals fails to induce circling activity. In contrast, administration of quinpirole elicited rotation toward the lesioned side, which was increased by concurrent injection of SKF 38393. This behavior was inhibited by pretreatment with either a specific D₁ (SCH 23390) or D₂ (-sulpiride) antagonist. The apomorphine also induced ipsilateral circling that was abolished by pretreatment with D₁ or D₂ antagonists. The above results suggest that coactivation of both D₁ and D₂ striatal dopamine receptors are necessary to induce rotation in this normosensitive model.     

Dopamine D1 receptors are involved in the modulation of D2 receptors induced by cholecystokinin receptor subtypes in rat neostriatal membranes

The action of cholecystokinin octapeptide (CCK-8) on rat neostriatal dopamine (DA) D₂ receptors was evaluated in membrane binding experiments. 0.1 nM of CCK-8 inreased theK_d value of the D₂ agonist [³H]N-propylnorapomorphine (NPA) binding sites by 42%. The CCK_B antagonist PD134308 blocked this action. Kinetic analysis demostrated that this effect of CCK-8 was related to a reduction by 45% of the association rate constant of [³H]NPA. In contrast, 1 nM of CCK-8 decreased theK_H and theK_L values of DA for the D₂ antagonist [³H]raclopride binding sites by 56% and 50%, respectively. Both the CCK_A antagonist L364718 and the CCK_B antagonist PD134308 blocked this effect. The D₁ antagonist SCH23390 counteracted the CCK-8 induced decrease in theK_H and theK_L values of DA, and allowed 1 nM of CCK-8 to produce a significant increase in the IC₅₀ value of NPA for the [³H]raclopride binding sites. These results indicate that CCK-8 can reduce the affinity of the neostriatal D₂ agonist binding sites, but increase the affinity of D₂ receptors for DA. D₁ receptors may exert a switching role in the modulation of the neostriatal D₂ receptors by the CCK receptors.     

Dopamine D2 receptor-mediated G-protein activation in rat striatum: functional autoradiography and influence of unilateral 6-hydroxydopamine lesions of the substantia nigra.

Unilateral 6-hydroxydopamine (6-OHDA) lesions of substantia nigra pars compacta (SNPC) neurons in rats induce behavioural hypersensitivity to dopaminergic agonists. However, the role of specific dopamine receptors is unclear, and potential alterations in their transduction mechanisms remain to be evaluated. The present study addressed these issues employing the dopaminergic agonist, quinelorane, which efficaciously stimulated G-protein activation (as assessed by [³⁵S]GTPγS binding) at cloned hD₂ (and hD₃) receptors. At rat striatal membranes, dopamine stimulated [³⁵S]GTPγS binding by 1.9-fold over basal, but its actions were only partially reversed by the selective D₂/D₃ receptor antagonist, raclopride, indicating the involvement of other receptor subtypes. In contrast, quinelorane-induced stimulation (48% of the effect of dopamine) was abolished by raclopride, and by the D₂ receptor antagonist, L741,626. Further, novel antagonists selective for D₃ and D₄ receptors, S33084 and S18126, respectively, blocked the actions of quinelorane at concentrations corresponding to their affinities for D₂ receptors. Quinelorane potently induced contralateral rotation in unilaterally 6-OHDA-lesioned rats, an effect abolished by raclopride and L741,626, but not by D₃ and D₄ receptor-selective doses of S33084 and S18126, respectively. In functional ([³⁵S]GTPγS) autoradiography experiments, quinelorane stimulated G-protein activation in caudate putamen and, to a lesser extent, in nucleus accumbens and cingulate cortex of naive rats. In unilaterally SNPC-lesioned rats, quinelorane-induced G-protein activation in the caudate putamen on the non-lesioned side was similar to that seen in naive animals (50% stimulation), but significantly greater on the lesioned side (80%). This increase was both pharmacologically and regionally specific since it was reversed by raclopride, and was not observed in nucleus accumbens or cingulate cortex. In conclusion, the present data indicate that, in rat striatum, the actions of quinelorane are mediated primarily by D₂ receptors, and suggest that behavioural hypersensitivity to this agonist, induced by unilateral SNPC lesions, is associated with an increase in D₂, but not D₃ or D₄, receptor-mediated G-protein activation.     

Presynaptic D2 dopaminergic receptors mediate inhibition of excitatory synaptic transmission in rat neostriatum

The effect of dopamine (DA) on excitatory synaptic transmission was studied in rat neostriatal neurons using intracellular- and whole-cell voltage clamp-recording methods. Depolarizing excitatory postsynaptic potentials (EPSPs) were evoked by cortical stimulation. Superfusion of DA (0.01–10 μM) reversibly decreases EPSP in a concentration-dependent manner and with a estimated IC₅ of 0.3 μM. In addition, the inhibitory effect induced by DA at a low concentratiion (0.1 μM) was antagonized by sulpiride (1–10 nM), a selective D₂ dopaminergic receptor antagonist. However, D₁ dopaminergic receptor antagonist SKF-83566 (1–5 μM) did not affect the blocking effect by DA 0.1 μM. Based on these findings, we conclude that DA at a low concentration ( 0.1 μM) reduced the excitatory response of neostriatal neurons following cortical stimulation via the activation of D₂, but not D₁ dopaminergic receptors, located on the terminals of corticostriatal neurons.     

Stimulation of both D1 and D2 dopamine receptors appears necessary for full expression of postsynaptic effects of dopamine agonists: a neurophysiological study

The abilities of 4 dopamine agonists to inhibit the tonic single unit activity of substantia nigra dopamine neurons and stimulate tonic activity of globus pallidus neurons were compared to study the agonists' effects on pre- and postsynaptic dopamine receptors, respectively. The agonists studied were apomorphine and pergolide, which interact with both D₁ and D₂ receptors, and the selective D₂ agonists quinpirole and RU 24926. Drugs were administered systematically. The 4 dopamine agonists were equipotent and equiefficacious at inhibiting the firing rates of dopamine neurons. In contrast, their effects on pallidal cells were not identical; apomorphine and pergolide induced significantly greater increases in pallidal cell activity than did quinpirole and RU 24926. In addition, pretreatment with a small dose of quinpirole did not attenuate the excitatory effect of apomorphine on globus pallidus cell activity, as low doses of apomorphine have previously been shown to do. Possible mechanisms underlying the differences in efficacy between the non-selective and D₂ selective dopamine agonists in the globus pallidus were investigated. Coadministering quinpirole with apomorphine did not significantly attenuate the effect of apomorphine, suggesting that quinpirole is not a partial agonist at postsynaptic dopamine receptors. In addition, prazosin pretreatment did not attenuate the stimulatory effect of pergolide on firing rates of pallidal cells, indicating that the greater efficacy of the non-selective agonists was not due to concurrent stimulation of ₁ adrenergic receptors and dopamine receptors. However, the effect of quinpirole on pallidal cell activity was significantly potentiated by pretreatment with the D₁ agonist RS-SKF 38393 but not its inactive enantiomer S-SKF 38393. These results suggest that concurrent D₁ and D₂ receptor stimulation may be necessary for the full expression of postsynaptic receptor-mediated effects of dopamine and dopamine agonists in the basal ganglia.     

Asymmetric elevation of striatal dopamine D2 receptors in the chakragati mouse: neurobehavioral dysfunction in a transgenic insertional mutant.

We have previously reported the discovery of a transgenic insertional mutant, recently named the chakragati (ckr) mouse, which displays lateralized circling, locomotor hyperactivity, hyperreactivity, as well as body weight deficits. Since lateralized dopamine function is associated with circling behavior we sought to determine whether dopamine (DA) D₁ and D₂ receptors were asymmetrically distributed in the striata of adolescent and adult ckr mice using receptor autoradiography. Stereotypic and rotational responses to quinpirole served as behavioral indices of D₂ receptor function. The ckr mice showed hemispherically asymmetric elevations in DA D₂ receptors in the lateral subregions of the striatum whereas medial regions of the striatum were symmetrically and bilaterally elevated (overall elevation = 30%). As a group,ckr mice had higher D₂ receptor levels on the side which was contralateral to the preferred direction of spontaneous nocturnal rotation. Striatal D₁ receptors and mesolimbic D₂ and D₁ receptors of ckr mice were neither elevated nor differentially asymmetric. Young adult ckr mice showed dose-dependent increases in net rotations in response to quinpirole whereas normal mice showed no change from baseline levels. Both groups showed similar stereotypic responses. Older adult ckr mice, however, showed dose-dependent reductions in rotation after quinpirole whereas normal mice turned at baseline levels. Older ckr mice also displayed significantly greater stereotyped sniffing behavior. This unique mutant provides a novel genetic model of basal ganglia dysfunction, and may be useful in studying aspects of neuropsychiatric disorders associated with dopaminergic abnormalities.     

Dopamine receptor-mediated regulation of corticotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus

The present study examined the effects of intraperitoneal administration of selective D1 (SKF 38393) and D2 (quinelorane) dopaminergic receptor agonists on Fos-like immunoreactivity (Fos-LI) and levels of corticotropin-releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus (PVN) and in the central nucleus of the amygdala (cAMY). Ninety minutes after administration of the D1 agonist SKF 38393, Fos-LI was increased in both the PVN and cAMY. Administration of SCH 39166, a selective D1 antagonist, blocked and attenuated the SKF 38393-induced increase in Fos-LI in the PVN and cAMY, respectively. Similarly, 90 minutes after intraperitoneal injection of the D2 agonist quinelorane, Fos-LI was increased in both PVN and cAMY. Administration of the selective D2 antagonist raclopride prevented the ability of quinelorane to increase Fos-LI in the PVN and cAMY. Both SKF 38393 and quinelorane stimulated the expression of CRH mRNA in the PVN, but failed to alter its expression in the cAMY. Taken together, these results indicate that stimulation of either D1 or D2 dopaminergic receptors activates CRH neurons in the PVN. Stimulation of either D1 or D2 receptors activates neurons in the cAMY, but these changes do not appear to be occurring in CRH neurons.     

The neuroleptic-like peptide desenkephalin-γ-endorphin does not antagonize the dopamine receptor agonist-induced inhibition of the release of [H]dopamine from rat nucleus accumbens slices in vitro

In rats, the non-opioid β-endorphin (βE) fragment desenkephalin-γ-endorphin (DEγE, βE_6–17) antagonizes the hypomotility induced by a small dose of dopamine (DA) receptor agonists. It has been suggested that DEγE might act in this respect by a direct or indirect blockade of presynaptically located DA receptors in the nucleus accumbens, thereby causing an increase of DA release. Therefore in the present study the effect of DEγE was examined on DA receptor agonist-induced inhibition of the electrically evoked release of previously accumulated [³H]DA from rat nucleus accumbens slices in vitro. The DA receptor agonists apomorphine, LY 171555 andn,n-di-n-propyl-7-hydroxy-2-aminotetralin (DP-7-AT) inhibited in a concentration-dependent manner the electrically evoked release of [³H]DA. The selective D₂ receptor antagonist (−)-sulpiride blocked the effects of apomorphine, corroborating that the DA receptor involved is of a D₂ type. DEγE was tested at several concentrations (10⁻⁹–10⁻⁶) and under various experimental conditions. DEγE, by itself, did not affect either the electrically stimulated or the basal release of [³H]DA. The inhibiting effect of DA receptor agonists was slightly reduced by DEγE, but this effect was present in some experiments only. It is concluded that DEγE does not function as an antagonist for the DA receptor mediating DA release and that the interaction observed in behavioural experiments between DA agonists and DEγE does not occur at the level of this receptor.     

Effects of prolactin on expression of Fos-related antigens in tyrosine hydroxylase-immunoreactive neurons in subdivisions of the arcuate nucleus

Dual immunohistochemistry was employed to determine the effects of prolactin on expression of Fos and its related antigens (FRA) in tuberoinfundibular dopamine (TIDA) neurons located in the dorsomedial (DM) and ventrolateral (VL) subdivisions of the arcuate nucleus (ARC) in the male rat. Systemic administration of the DA receptor antagonist haloperidol caused a sustained (up to 12 h) increase in plasma prolactin concentrations that was accompanied by a transient increase (at 3 h) in the percentage of tyrosine hydroxylase (TH)-immunoreactive (IR) neurons containing FRA-IR nuclei in the DM-ARC. In contrast, haloperidol caused a prolonged (1. 5 to 12 h) decrease in the percentage of TH-IR neurons with FRA-IR nuclei in the VL-ARC. Haloperidol had no effect, however, on the overall number of TH-IR neurons in either of these regions. Co-administration of prolactin antisera (PRL-AB) blocked haloperidol-induced increases in both plasma prolactin concentrations and the percentage of TH-IR neurons expressing FRA in the DM-ARC, but had no effect on haloperidol-induced inhibition of FRA expression in TH-IR neurons in the VL-ARC. Intracerebroventricular (i.c.v.) administration of prolactin also increased the percentage of TH-IR neurons containing FRA-IR nuclei in the DM-ARC, but this effect was of longer duration (up to 6 h) than that of haloperidol in all but the most caudal portion of the DM-ARC. In the VL-ARC, prolactin caused a transient increase (at 1.5 h) in the percentage of TH-IR containing FRA-IR nuclei. These results demonstrate that prolactin regulates immediate early gene expression in TIDA neurons in male rats, and reveal that there are temporal differences in the responsiveness of discrete subpopulations of these neurons to prolactin. Prolactin causes a short-lived increase in FRA expression in TIDA neurons in the VL-ARC which is followed by a more prolonged activation of FRA expression in TIDA neurons in the DM-ARC.     

Pharmacological characterization of grooming induced by a selective NK-1 tachykinin receptor agonist

Bilateral intranigral administration of the selective NK-1 tachykinin receptor agonist [AcArg⁶, Sar⁹, Met(O₂)¹¹]SP_6–11 (0–11 nmol total bilateral dose) selectively induced grooming in rats. This response was blocked by concurrent intranigral administration of the NK-1 tachykinin receptor antagonist RP 67580 (2 nmol), but not by NK-2 (L-659, 877) or NK-3 ([Trp⁷, β-Ala⁸]NKA_4–10) antagonists. Pretreatment with systemic opioid (naloxone 1.5 mg/kg) and D₁ dopamine (SCH 23390 100 μg/kg) receptor antagonists also attenuated tachykinin-induced grooming, which was unaffected by D₂ dopamine (sulpiride 30 mg/kg) or 5-HT_2A+C (ritanserin 2 mg/kg) antagonists. Grooming induced by intranigral [AcArg⁶, Sar⁹, Met(O₂)¹¹]SP_6–11 was also attenuated by bilateral 6-hydroxydopamine lesions of te substantia nigra. These findings indicate that grooming induced by intranigral tachykinins reflects activation of NK-1 receptors and is dependent upon endogenous dopamine and consequent selective stimulation of D₁ dopamine receptors.     

SKF 38393 alters the rate-dependent D2-mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single-unit recording techniques to examine whether SKF 38393 can alter D2-mediated inhibition of DA cell activity. Quinpirole-induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole-induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl-specific, feedback pathway-dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2-mediated inhibition of cell firing rate.     

Neurotrophic factor for serotonergic neurons prevents degeneration of grafted raphe neurons in the cerebellum.

[³H]SCH 23390 binds stereospecifically and with high affinity to D₁ dopaminergic receptors in the developing chick retina. Autoradiographic experiments revealed that in retinas from 3-day-old chicken and embryos with 12, 14 and 16 days of development, specific labeling of [³H]SCH 23390 was mainly observed over the plexiform layers of the tissue, showing that dopaminergic D₁ receptors are localized in retina cell neurites since the initial stages of neurite formation. The total number of [³H]SCH 23390 binding sites increased 5-fold during the differentiation of the retina, while the dopamine-dependent cyclic adenosine monophosphate (AMP) accumulation was significantly decreased. Consequently, the ratio between dopamine-dependent cyclic AMP accumulation and [³H]SCH 23390 binding sites decreased 10-fold as retina differentiated, indicating that a significant portion of D₁ receptors in retinas from adult chicken are not effectively coupled to adenylate cyclase molecules.     

Striatal dopamine innervation and receptor density: regional effects of the weaver mutation

Mice homozygous for the autosomal recesive gene weaver (wv) exhibit a regionally specific depletion of forebrain dopamine (DA). DA is reduced approximately 70% in the dorsal striatum of homozygotes (wv/wv) relative to heterozygous (+/wv) controls while DA content in ventral striatum is relatively unchanged. The goal of the present study was to determine the regional effects of the weaver mutation on striatal DA receptors and DA uptake sites using quantitative autoradiography. Catecholamine histofluorescence was used to examine midbrain DA-containing cell bodies. Compared to behaviorally normal (+/-) littermates, the binding of [³H]spiroperidol to D₂ sites was significantly increased in the dorsal but not ventral striatum of wv/wv mice. Binding of the D₁ ligand, [³H]SCH23390, was significantly decreased throughout the striatum of wv/wv mice. The binding of [³H]mazindol to DA uptake sites was dramatically reduced in all wv/wv striatal regions except the ventrolateral portion. Compared to +/-littermates, wv/wv mice had far fewer fluorescent cell bodies in the substantia nigra and a less pronounced reduction of ventral tegmental area fluorescent somata. These findings support the hypothesis that heterogeneities exist in the genetic control of the mesotelencephalic DA system. The results underscore the usefulness of the weaver mouse in the study of mesostriatal sub-systems, receptor regulation, and potentially as a model of human neuropathologies that affect distinct populations of cells in the mesotelecephalic system.     

Sequential changes of dopaminergic receptors in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle

We investigated the sequential patterns of changes in dopamine uptake sites, D₁ and D₂ receptors in the brain of animals lesioned with 6-hydroxydopamine using quantitative receptor autoradiography. The rats were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. Degeneration of the nigrostriatal pathway caused a significant loss of dopamine uptake sites in the ipsilateral striatum, substantia nigra (SN) and ventral tegmental area (VTA) in the lesioned animals. Dopamine D₁ receptors were significantly increased in the ventromedial part of striatum of the ipsilateral side from 2 to 4 weeks postlesion. In the ipsilateral SN, a transient increase in dopamine D₁ receptors was observed only 1 week after lesioning. However, the frontal cortex, parietal cortex and dorsolateral part of the striatum showed no significant change in dopamine D₁ receptors throughout the experiments. On the other hand, dopamine D₂ receptors were decreased increased in the ipsilateral SN and VTA from 1 week to 8 weeks postlesion. In the ipsilateral striatum, dopamine D₂ receptors were increased in the dorsolateral part from 2 weeks to 8 weeks and in the ventromedial part from 2 weeks to 4 weeks. However, the frontal cortex and parietal cortex showed no significant change in dopamine D₂ receptors during postlesion. In the contralateral side, most of regions examined showed no significant change in dopamine uptake sites, dopamine D₁ receptors and dopamine D₂ receptors during postlesion except for a transient change in a few regions. These results demonstrate that 6-hydroxydopamine can cause a severe functional damage in dopamine uptake sites in the striatum, SN and VTA. Our findings also suggest that the up-regulation in dopamine D₂ receptors is more pronounced than that in dopamine D₁ receptors in the brain after 6-hydroxydopamine treatment. Furthermore, our results support the existence of dopamine D₂ receptors on the neurons of SN and VTA. Thus, our findings provide insights into the pathogenesis of Parkinson's disease.     

Limbic pallidal adaptations following long-term cessation of dopaminergic transmission: lack of upregulation of dopamine receptor function

Neurons in the ventral pallidum (VP) exhibit robust responding to activation of dopamine (DA) receptors of the D1 class. To determine if the VP adapts to chronic cessation of DA transmission, the present studies examined D1 receptor-mediated responses in the VP recorded extracellularly in chloral-hydrate anesthetized rats following destruction of DA neurons with 6-hydroxydopamine (6-OHDA) or long-term treatment with the D1 antagonist SCH23390. Indices of basal spiking (i.e., spontaneous firing rate and pattern) recorded 10-21 days after unilateral 6-OHDA treatment did not differ from controls. Moreover, DA depletion did not alter the proportion of VP neurons whose rate was enhanced with i.v. injections of the D1 agonist SKF38393, and the functional efficacy (Emax) and potency (ED50) were similar to controls. There also was no change in the direction of responses, the Emax or the ED50 measure of sensitivity (ECur50) to iontophoretic application of DA or SKF38393 in VP neurons. Forty-eight hours after 21 once-daily treatments with SCH23390, the number of [3H]SCH23390-labeled D1 receptors was increased in the striatum, but unchanged in the VP, globus pallidus, or septum. Accordingly, there was no functional upregulation of VP responses to i.v. SKF38393. Indeed, the proportion of SKF38393-sensitive neurons was decreased after chronic SCH23390. Distinguishing the VP from other forebrain regions, these findings indicate that basal spiking is not altered in the VP following chronic DA depletion, and that no upregulation of VP DA receptor function occurs following either dopaminergic lesions or chronic antagonism of D1 receptors.     

Dopamine D2 agonist-induced behavioural depression is reversed by dopamine D1 agonists

Summary The dopamine (DA) D2 agonist bromocriptine produced dose-dependent locomotor depression in mice with intact stores of DA, as measured in automated activity cages. The DA D1 agonist CY208-243, reversed the bromocriptine-induced depression. Using direct observational analysis, another selective DA D2 agonist, quinpirole, induced dose-dependent depression and this was reversed by the D1 agonist SKF38393. The effect of SKF38393 could be blocked by prior pretreatment with SCH23390. It is concluded that DA D2 agonist-induced locomotor depression is mediated via a DA D2 autoreceptor-mediated inhibition of DA release onto postsynaptic DA receptors. This reduction in release probably deprives postsynaptic D1 and D2 receptors of endogenous DA. However, since bromocriptine (and probably quinpirole) in all likelihood occupies both pre- and postsynaptic D2 receptors immediately on injection, and since CY208-243 and SKF38393 (respectively) could reverse the depression, the depression seems to be due specifically to a deprivation of DA at postsynaptic D1 receptors.     

Effects of dopamine agonists on excitatory inputs to nucleus accumbens neurons from the amygdala: modulatory actions of cholecystokinin

The interaction of the cholecystokinin octapeptide (CCK-8) with dopamine (DA) and dopamine agonists on neurons in the nucleus accumbens was investigated using single unit recording and iontophoretic techniques in urethane-anaesthetized rats. Neurons in the nucleus accumbens were activated by single pulse stimulation of amygdala. Using seven-barrel microelectrodes, the effects of iontophoretic application of CCK-8, DA, dopamine D1 and/or D2 receptor agonists (SKF 38393 and LY 171555 respectively) were compared. The iontophoretic application of DA, LY 171555 and LY 171555 + SKF 38393 attenuated by 50-60% the excitatory responses of accumbens neurons to electrical stimulation of basolateral amygdala whereas SKF 38393 attenuated the response by less than 30%. The iontophoretic application of CCK reduced these attenuating effects of DA, LY 171555 and SKF 38393 + LY 171555. With CCK there was a rather small reduction of the attenuating effect of SKF 38393. These observations provide additional electrophysiological evidence of the interaction of CCK and dopamine and suggest that the interaction is associated mainly with dopamine D2 mechanisms.     

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.     

D1 dopamine receptor stimulation inhibits firing activity of midbrain dopamine neurons in reserpine treated rats: An effect eliminated after hemitransection of diencephalon

It has been reported that systemic administration of the D₁ dopamine (DA) receptor agonist SKF 38393 inhibits the firing rate of substantia nigra pars compacta (SNC, A9) DA neurons after repeated reserpine treatment in locally anesthetized rats, although SKF 38393 induces little effect on the firing of midbrain DA neurons in normal rats. The present study found that local pressure microejection of SKF 38393 (10⁻² M, 20–100 nl) to SNC or substantia nigra pars reticulata (SNR) failed to influence the firing of SNC DA neurons in reserpinized rats (reserpine 1 mg/kg × 6 days, s.c.); subsequent intravenous (i.v.) injection of SKF 38393 (4 mg/kg), however, inhibited their firing and the inhibition was reversed by the D₁ receptor antagonist SCH 23390. Similarly, systemic administration of SKF 38393 (4 mg/kg, i.v.) inhibited the firing of ventral tegmental area (VTA, A10) DA cells in reserpinized rats, while local microejection of SKF 38393 (10⁻² M, 30–60 nl) did not affect their firing. Furthermore, the inhibitory effect of systemic SKF 38393 on firing rate of either SNC or VTA DA neurons in reserpinized rats was eliminated after hemitransection of diencephalon. These results suggest that repeated reserpine treatment renders midbrain DA neurons responsive to D₁ receptor stimulation and that D₁ receptor agonist-induced inhibition of midbrain DA cell firing in reserpinized rats may require the involvement of long-loop feedback pathways. © 1996 Wiley-Liss, Inc.     

Dopamine antagonists induce fos-like-immunoreactivity in the substantia nigra and entopeduncular nucleus of the rat

Injections of the D₂ receptor antagonists haloperidol (0.5–8 mg/kg) and metoclopramide (6.25–50 mg/kg) in rats resulted in a dose dependent induction of Fos-like-immunoreactivity in the rostral portion of the entopeduncular nucleus (EPN) and in the medial portion of the pars reticulata of the substantia nigra (SNpr). Nigral staining occurred exclusively in neurons which were not immunoreactive for tyrosine hydroxylase and could be antagonized by pretreatment with the anticholinergic drug scopolamine (3 mg/kg). Effects were much less pronounced following injections of the selective D1 antagonist SCH-23390 (2–8 mg/kg). No staining could be observed following administration of the 5HT₃ antagonist MDL-72222 (10 mg/kg) or the 5HT₁/5HT₂ antagonist metergoline (5 mg/kg), suggesting that the effects observed with dopamine antagonists were not secondary to actions at serotonin receptors. These results are consistant with the hypothesis that blockade of dopamine receptors results in a disinhibition of cells within the SNpr and EPN and further suggest that examination of immediate-early gene expression may provide a useful tool for studying the extrastriatal circuitry engaged by manipulations of dopaminergic transmission.